Many naturally occurring organic compounds have an optically active configuration. Among these, there are many organic compounds with physiological activity in which only one optical isomer has a desirable activity. Regarding the other optical isomer, which does not have a desirable activity, there are also known cases in which the optical isomer is not only devoid of a useful physiological activity for organisms, but in which it has even toxicity towards organisms. Therefore, as safe method for synthesizing pharmaceuticals and to produce a target compound or its intermediates, it is desirable to develop a method of synthesizing optically active compounds having a high optical purity.
Optically active alcohols are useful as an asymmetric source for synthesizing various optically active substances. Typically, optically active alcohols are produced by optical resolution of racemic compounds or by asymmetric synthesis using a biological catalyst or an asymmetric metal complex as a catalyst. In particular, the production of optically active alcohol by asymmetric synthesis is a technology which is recognized to be indispensable for producing optically active alcohols on a large scale.
Optically active quinuclidinols having one or more substituted groups at the 2-position, which are synthetic intermediates of optically and physiologically active compounds used for medicine, agrichemicals, etc., are one type of industrially useful optically active alcohols. For example, optically active 2-(3-pyridylmethyl)-3-quinuclidinol is a synthetic intermediate of nicotinic cholinergic receptor inhibiting substances which is useful in various therapies of disorders of the central nervous system (Patent Documents 1 and 2). Moreover, optically active 2-diphenylmethyl-3-quinuclidinol is a synthetic intermediate of a Substance P antagonist which is effective in therapies such as the treatment of disorders of the central nervous system and senile dementia of Alzheimer type (Patent Documents 3-6). Furthermore, a multitude of different physiological activities are reported for the compound in which the hydroxyl group at the 3-position is substituted by an amino group (Patent Document 7).
As mentioned hereinafter, methods for optically resolving racemic cis-quinuclidinol have been reported as method of producing optically active 3-quinuclidinol having one or more substituted groups at the 2-position. For example, according to Non-Patent Document 1, a method is known wherein the target substance is obtained by reacting racemic 2-arylmethyl-3-quinuclidinol with optically active 2-methoxy-2-phenylacetic acid to obtain diastereomers, followed by HPLC resolution and then hydrolysis; according to Non-Patent Document 2, a method is known wherein the target substance is obtained by reacting racemic 2-diarylmethyl-3-quinuclidinol with optically active mandelic acid for conversion into diastereomers, followed by resolution by recrystallization and then hydrolysis; according to Non-Patent Document 3, a method is known wherein the target substance is obtained by reacting racemic 2-diarylmethyl-3-quinuclidinol with optically active camphoric acid to obtain diastereomers, followed by resolution through recrystallization and then hydrolysis. However, these methods are complicated since they require the prior production of racemic quinuclidinol having one or more substituted groups at the 2-position and the conversion into diastereomers, which then needs to be followed by further processes such as resolution and deprotection.
Moreover, these methods are means for obtaining the target optical isomers by optical resolution of racemic 3-quinuclidinol having one or more substituted groups at the 2-position; since the other, non-target, optical isomer is left over, it is not possible to obtain a high yield. Consequently, it can hardly be said that these methods are simple and economic methods for producing optically active 3-quinuclidinol having one or more substituted groups at the 2-position.
On the other hand, a known method for obtaining optically active alcohol is the asymmetric hydrogenation of prochiral carbonyl compounds in the presence of an asymmetric metal complex catalyst. Patent Document 8 discloses a method for asymmetrically hydrogenating carbonyl compounds in the presence of a ruthenium metal complex having an optically active diphosphine compound such as BINAP, a base such as hydroxide of alkali earth metal, alkali metal, and an ethylenediamine-type optically active diamine compound. Patent Document 9 further discloses a method for hydrogenating carbonyl compounds using a ruthenium complex having optically active phosphine such as BINAP and an optically active 1,2-ethylenediamine-type ligand as catalyst. Patent Document 10 further discloses a method using a ruthenium complex having an optically active phosphine such as SKEWPHOS and an optically active 1,2-ethylenediamine-type ligand.
As method of synthesizing optically active 3-quinuclidinol using these asymmetric hydrogenation methods, Patent Document 11 mentions a method of hydrogenation of a quinuclidinone derivative selected from compounds consisting of 3-quinuclidinone, its adduct to a Lewis acid and the specific tertiary and quaternary salts corresponding thereto in the presence of a rhodium, iridium or ruthenium complex having a chiral diphosphine. Patent Document 12 discloses a method for producing optically active 3-quinuclidinol by hydrogenating 3-quinuclidinone in the presence of a base and an optically active ruthenium complex having an optically active bidentate ligand and an optically active 1,2-ethylenediamine-type ligand. Patent Document 13 further discloses a method for hydrogenating 3-quinuclidinone by using, as catalyst, a rhodium complex having an optically active phosphine having a ferrocene skeleton and a 1,2-ethylenediamine-type ligand. In this Patent Document, even though prochiral ring ketones which may have a substitution group such as 3-quinuclidinone is described, no specific examples of 3-quinuclidinone having a substitution group at the 2-position is described. In other words, these documents all report how to obtain 3-quinuclidinol by reduction of 3-quinuclidinone not having a substitution group at the 2-position, without any mention whatsoever of an example of synthesizing optically active 3-quinuclidinol having a substitution group at the 2-position from a racemic 3-quinuclidinone having a substitution group at the 2-position.
Moreover, regarding catalytic asymmetric hydrogenation, methods using alcohol and formic acid as reducing agent, i.e. catalytic asymmetric reduction reaction, are also frequently reported. In particular, the properties of an asymmetric ruthenium catalyst having an amine ligand with a sulfonylamide group as anchor (Patent Document 14) ought to be specifically mentioned. Apart from this, a similar catalytic system with a ruthenium-amine complex as basic skeleton is also reported (Non-Patent Document 4). Moreover, in the same way, rhodium and iridium catalysts with a metal-amine bond are also reported (Non-Patent Document 5). However, these documents report no example of synthesizing optically active 3-quinuclidinol having one or more substituted groups at the 2-position by asymmetric reduction of 3-quinuclidinone having one or more substituted groups at the 2-position or even a method for synthesizing optically active 3-quinuclidinol by asymmetric reduction of 3-quinuclidinone not having one or more substituted groups.
Further, regarding asymmetric reduction accompanying dynamic kinetic resolution, Patent Document 15 reports synthesis of optically active hydrobenzoin from racemic benzoin, but does not report an example of reaction by synthesizing optically active 3-quinuclidinol from racemic 3-quinuclidinone having a substitution group at the 2-position.
As shown above, a method for synthesizing optically active 3-quinuclidinol having one or more substituted groups at the 2-position by asymmetric reduction of quinuclidinone having one or more substituted groups at the 2-position and by using a reduction technique has not hitherto been known.    Patent Document 1: JP, A, 2002-531564    Patent Document 2: WO 2000-0034276    Patent Document 3: Japanese Patent No. 3273750    Patent Document 4: European Patent No. 829480    Patent Document 5: Japanese Patent No. 2500279    Patent Document 6: European Patent No. 499313    Patent Document 7: JP, A, 2002-020287    Patent Document 8: JP, A, 8-225466    Patent Document 9: JP, A, 11-189600    Patent Document 10: JP, A, 2003-252884    Patent Document 11: JP, A, 9-194480    Patent Document 12: JP, A, 2003-277380    Patent Document 13: JP, A, 2004-292434    Patent Document 14: JP, A, 11-322649    Patent Document 15: Japanese Patent No. 3630002    Non-Patent Document 1: Bioorg & Med. Chem. Lett. 15, 2073-2077 (2005)    Non-Patent Document 2: J. Med. Chem. 17, 497-501 (1974)    Non-Patent Document 3: Bioorg & Med. Chem. Lett. 8, 1703-1706 (1993)    Non-Patent Document 4: Organometallics 1996, 15, 1087.    Non-Patent Document 5: J. Org. Chem. 1999, 64, 2186.